Retinol binding protein 4 (hereinafter sometimes to be abbreviated as “RBP4”) is known to be a sole blood retinol transport protein mainly produced in the liver.
In recent years, moreover, RBP4 is suggested to be a factor inducing insulin resistance, as shown below.
(1) Since RBP4 expression increases in the adipocytes of GLUT4 knockout mouse showing insulin resistance, RBP4 is suggested to be a potential adipocytokine inducing insulin resistance (see Nature 436, 356-362 (2005) (non-patent document 1)).
(2) RBP4 overexpression mouse shows hyperglycemia and hyperinsulinemia, and RBP4 knockout mouse shows promotion of glucose tolerance and insulin sensitivity as phenotype (see Nature 436, 356-362 (2005) (non-patent document 1)).
(3) Mouse bred on a high-fat diet shows high blood RBP4 value, which is correlated with induction of insulin resistance (see Nature 436, 356-362 (2005) (non-patent document 1)).
(4) Disease model mouse showing diabetes and obesity pathology such as ob/ob mouse, 11β-HSD1 overexpression (adipose tissue specific) mouse, MC4R knockout mouse, GLUT4 knockout (adipose tissue and skeletal muscle specific) mouse and the like also shows high blood RBP4 value (see Nature 436, 356-362 (2005) (non-patent document 1)).(5) It has been reported that blood RBP4 concentration and insulin sensitivity and sugar disposal rate are inversely correlated in human. The glucose infusion rate decreases as the blood RBP4 concentration increases in euglycemic hyperinsulinemic glucose clamp test (see Cell Metab., 6, 79-87 (2007) (non-patent document 2)).(6) While exercise is known to improve insulin sensitivity, an extremely high correlation between such an improving effect and lowering of blood RBP4 concentration is shown (see N. Engl. J. Med., 354, 2552-2563 (2006) (non-patent document 3)).(7) WO 2005/059564 (patent reference 1) describes that a compound that controls RBP4 activity is useful for the treatment of insulin resistance.
RBP4 is stably present in blood in the form of a complex resulting from the binding of retinol and TTR (transthyretin). When RBP4 is dissociated from TTR and becomes free, it is decomposed in and excreted from the kidney comparatively rapidly. Fenretinide, a retinol derivative, inhibits the binding of RBP4 and retinol, and consequently inhibits formation of a complex with TTR. It is known that administration of fenretinide to animal induces lowering of blood RBP4 (see Biochim. Biophys. Acta, 1294, 48-54 (1996) (non-patent document 4)).
From such foregoing findings, a compound that inhibits formation of a complex of RBP4 and TTR by inhibiting the binding of RBP4 and retinol is expected to lower blood RBP4 concentration and consequently induce correction of hyperglycemia and improvement of insulin resistance.
As mentioned above, a compound capable of lowering blood RBP4 concentration can be a therapeutic drug for diabetes.
In recent years, moreover, a report has documented that blood RBP4 value and blood TG (triglyceride) or LDL cholesterol value positively correlate in human, and blood RBP4 value negatively correlates with HDL cholesterol value (see J. Atheroscler. Thromb., 13, 209-215 (2006) (non-patent document 5), N. Engl. J. Med., 355, 1392-1395 (2006) (non-patent document 6), Diabetes, 56 (Supplement 1), A378 (1477-P) (2007) (non-patent document 7)), thus suggesting relationship between RBP4 and lipid metabolism.
In view of the above, a medicament having an action to lower blood RBP4 value (concentration) (also referred to as “RBP4 lowering action” in the present specification) (also referred to as “RBP4 lowering agent” in the present specification) can be an agent for the prophylaxis or treatment of hyperlipidemia.
As mentioned above, a medicament having an action to lower blood RBP4 value (concentration) (also referred to as “RBP4 lowering action” in the present specification) (also referred to as “RBP4 lowering agent” in the present specification) can be widely applicable to lifestyle-related diseases (diabetes, hyperlipidemia and the like).
As the compound having a structure similar to that of the compound of the present invention, the following compounds are known.
1) WO 03/031984 (patent document 2) discloses the following compound.
2) Zhongguo Yaoke Daxue Xuebao (1991), 22(6), 330-3 (non-patent document 8) discloses the following compound.
CAS registry No.: 143247-34-13) The following compounds are registered in the STN database.
CAS registry No.: 736168-64-2
CAS registry No.: 452358-00-8

CAS registry No.: 1094556-59-8
4) US 2004/116417 (patent document 3) discloses the following compound.
whereinR1 is an aromatic ring group (the aromatic ring group is optionally substituted by halogen, C1-4 alkoxy, C1-4 alkyl (including cyclic alkyl), C1-4 alkylthio, nitro, trifluoromethyl, trifluoromethoxy, methylenedioxy, an optionally substituted nitrogen-containing heterocyclic group and the like);R2 is hydrogen, C1-3 alkyl (optionally substituted by an optionally esterified carboxylic acid) or the like; andR3 and R4 are independently hydrogen or C1-4 alkyl.5) WO 2006/043064 (patent document 4) discloses the following compounds.
6) WO 95/33719 (patent document 5) discloses the following compounds.
7) EP 200415 A (patent document 6) discloses the following compounds.
8) JP-A-02-053780 (patent document 7) discloses the following compound.

However, it has not been reported that the above-mentioned compound has a RBP4 lowering action.